Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current...
Transcript of Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current...
![Page 1: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/1.jpg)
Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives thereof as bioisosteres of the carboxylic acid functional group Lassalas, P.; Oukoloff, K.; Makani, V.; James, M.; Tran, V.; Yao, Y.; Huang, L.; Vijayendran, K.; Monti, L.; Trojanowski, J. Q.; Lee, V. M.-Y.; Kozlowski, M. C.; Smith, III, A. B.; Brunden, K. R.; Ballatore, C. ACS Med. Chem. Lett. ASAP Celeste Alverez Current Literature 8/5/2017
8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
1
![Page 2: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/2.jpg)
Isosteres in Medicinal Chemistry
u Recent definition:
“Similarities must exist between at least some of the properties of the isostere and those of the fragment being replaced, such that the new analogs retain the biological activities of the parent compound.”
“At the same time, however, the isosteric replacement must produce changes in the physicochemical properties or susceptibility to metabolism compared to the parent compound in order to lead to improved derivatives.”
u Lassalas et al. J. Med. Chem. 2016, 59, 3183-3203.
8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
2
![Page 3: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/3.jpg)
Carboxylic acid Isosteres u Many reported in literature 8/5/2017
Ce
leste
Alve
rez @
Wip
f Gro
up
3
Lassalas et al. J. Med. Chem. 2016, 59, 3183-3203.
![Page 4: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/4.jpg)
Carboxylic acid Isosteres 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
4
Lassalas et al. J. Med. Chem. 2016, 59, 3183-3203.
![Page 5: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/5.jpg)
Carboxylic acid Isosteres 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
5
Lassalas et al. J. Med. Chem. 2016, 59, 3183-3203.
![Page 6: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/6.jpg)
Carboxylic acid Isosteres 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
6
Lassalas et al. J. Med. Chem. 2016, 59, 3183-3203.
![Page 7: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/7.jpg)
Oxetanes as Isosteres 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
7
Lassalas et al. ACS Med. Chem. Lett. ASAP
# o
f Exam
ple
s as Iso
sete
r in Lite
ratu
re
![Page 8: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/8.jpg)
Oxetanes in Medicinal Chemistry 8/5/2017
Ce
leste
Alve
rez @
Wip
f Gro
up
8
u Modulate lipophilicity
u Improve solubility, stability
R logD Solubility (μM) Clint (h/m) pKa
CH2 1.8 250 37/520 9.9
gem Me2 2.5 <4 16/420 9.9
oxetane 0.8 18,000 0/43 9.9
Carreira et al. J. Med. Chem., 2010, 53, 3227.
Wipf et al. ACS Med. Chem. Lett. 2014, 5, 900.
aq. solubility = 580 μM aq. solubility = 44,000 μM
![Page 9: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/9.jpg)
Recent Uses of Oxetanes as non-classical Isosteres 8/5/2017
Ce
leste
Alve
rez @
Wip
f Gro
up
9
u Recently Carreria and Shipman groups have utilized oxetanes to mimic amides and esters
Möller et al. Org. Lett. 2017, 19, 2510-2513.
![Page 10: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/10.jpg)
Synthesis
8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
10
Lassalas et al. ACS Med. Chem. Lett. ASAP
![Page 11: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/11.jpg)
Properties of 4-membered Heterocycle Isosteres 8/5/2017
Ce
leste
Alve
rez @
Wip
f Gro
up
11
![Page 12: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/12.jpg)
Why modify Ibuprofen? 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
12
Martel-Pelletier et al. Ann. Rheum. Dis. 2003, 62, 501-509.
![Page 13: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/13.jpg)
Synthesis
8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
13
Lassalas et al. ACS Med. Chem. Lett. ASAP
![Page 14: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/14.jpg)
4-Membered Heterocycles in Ibuprofen Analogs
Cmpd PGE2/D2 Assay IC50 (μM)
LBT4 Assay IC50 (μM)
2 0.6 >100
17 31.8 >100
18 28.1 >100
7 34.1 8.4
8 >100 7.6
9 17.4 11.7
10 14.6 20.2
8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
14
![Page 15: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/15.jpg)
4-Membered Heterocycles in Ibuprofen Analogs 8/5/2017
Ce
leste
Alve
rez @
Wip
f Gro
up
15
Concentration-response of inhibition of 5-LOX derived LTB4 and COX-derived PGE2/PGD2 by 2 (left) and 10 (right)
Lassalas et al. ACS Med. Chem. Lett. ASAP
![Page 16: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/16.jpg)
Proposed binding modes 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
16
Lassalas et al. ACS Med. Chem. Lett. ASAP
COX-1 crystal structure (PDB: 1EQG)
![Page 17: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/17.jpg)
Proposed binding modes 8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
17
Lassalas et al. ACS Med. Chem. Lett. ASAP
COX-1 crystal structure (PDB: 1EQG)
![Page 18: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/18.jpg)
Isosteres of Carboxylic Acids 8/5/2017
Ce
leste
Alve
rez @
Wip
f Gro
up
18
Lassalas et al. ACS Med. Chem. Lett. ASAP
![Page 19: Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/Current Literature/Celeste_13.pdf · Carboxylic acid Isosteres ! Many reported in literature 3 Lassalas](https://reader031.fdocuments.net/reader031/viewer/2022011823/5edbd69fad6a402d66663f65/html5/thumbnails/19.jpg)
Conclusions
u The 4-membered heterocyclic replacements of the carbonyl of carboxylic acids lead to improved lipophilicity and permeability
u Decreased acidity
u All replacements show weaker H-bonding interactions
u Oxetan-3-ol and thietan-3-ol and related oxidized products can successfully act as bioisosteres of carboxylic acids
u Potentially especially useful for CNS applications
8/5/2017 C
ele
ste A
lvere
z @ W
ipf G
rou
p
19